Abstract. We propose an innovative structural biology approach to stimulate pre-erythrocytic malaria vaccine and drug development using integrated information from X-ray crystallography and cryoelectron tomography to develop a detailed molecular topography of the sporozoite surface. This work will provide a three-dimensional map of the native arrangement of two of the most critical surface proteins, (CSP) and thrombospondin-related anonymous protein (TRAP), and their most potent epitopes on the sporozoite surface. This work will also be of significance for providing insights into the structural mechanisms of parasite motility, cell invasion, and immune evasion. With the long term goal of stimulating rational malaria vaccine development and structure-based drug design, we have three specific aims. 1. We propose that CSP packs in a specific way to form the sporozoite sheath. CSP contains N-terminal, repeat, and thrombospondin type I repeat (TSR) domains. We will solve the crystal structure of the TSR domain of CSP, which differs significantly from the TSR domain in other proteins, in several different lattices. We hypothesize that we will find crystal lattices that mimic packing of the CSP TSR domain on the sporozoite surface. We will interpret the structure, including the presence of a putative &#945;-helix, in terms of its function in supporting stable, yet flexible, interactions between CSP molecules on the sporozoite surface. 2. We will solve the crystal structure of the tandem von Willebrand factor A (VWA) and TSR domains in TRAP. We wish to understand how ligand binding to TRAP mediates gliding motility and cell invasion. Structures will test the hypothesis that the VWA and TSR domains interact with one another in a manner conducive to conformational change transmitted by tensile force between the VWA domain and the cytoplasmic domain. 3. We will apply cryoelectron tomography to define ultrastructural details of the sporozoite surface. We expect to see three sheath layers corresponding to the N-terminal, repeat, and TSR domains, that differ in electron density and in packing. We expect to be able to use subtomogram averaging to analyze packing in the most membrane-proximal layer, and to compare this packing to that of the TSR domain in crystal lattices. We may also see islands of other molecules such as TRAP in a sea of CSP. Through complementary use of crystallography and cryolectron tomography and microscopy we plan to construct a model of the sporozoite sheath. These findings should provide important insights into how epitopes are shielded or exposed in the sheath at different times in the infection process, and how apicomplexans shield themselves from the immune system.